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M K Jenkins

Publications and source records attributed to M K Jenkins.

At least 55 records · Page 3Linked to original sources
PubMed1994

The role of anergy in peripheral T cell unresponsiveness.

When a T cell's encounter with specific antigen results in good signaling through the T cell antigen receptor yet does not lead to a proliferative response, the T cell enters a state of nonresponsiveness, or anergy. Anergy induction can result from a number of different situations, including antigen presentation by costimulation-deficient or "non-professional" antigen presenting cells, pharmacological blocking of T cell proliferation, or chronic stimulation of the T cell receptor by antigen. Anergy is a long-lived but temporary state characterized by a profound inability of the T cell to produce IL-2. Other effector functions may be affected to variable degrees. Anergy has been characterized most carefully under in vitro conditions, but several experimental models have demonstrated that T cells can also become anergic in vivo. This mechanism for tolerance induction may help to ensure that any mature autoreactive T cells which escape thymic deletion are unable to respond to host tissues. Furthermore, an understanding of the mechanism of anergy induction will most certainly lead to beneficial clinical applications, including improving graft acceptance and avoiding such deleterious immune responses as autoimmunity and allergy.

Animals↗
PubMed1994

Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo.

An adoptive transfer system was used to monitor physically the behavior of a trace population of TCR transgenic T cells in vivo. After subcutaneous injection of antigen in adjuvant, the antigen-specific cells accumulated first in the paracortical region of the draining lymph nodes, proliferated there for several days, and then moved into lymph node follicles, where they accounted for most of the T cells. They then disappeared slowly from the draining nodes, and the remaining cells were hypersensitive to antigenic stimulation in vitro. In contrast, when the antigen was introduced into the blood, the antigen-specific cells rapidly accumulated in the paracortical regions of all lymph nodes, proliferated there for a short time, but never entered follicles. Most of the cells then rapidly disappeared, leaving behind a population that was hyporesponsive to antigenic stimulation. These results provide a physical basis for the classical finding that antigen-specific memory and tolerance can be influenced by the form of antigen administration.

Animals↗
PubMed1994

Prolonged survival without posttransplant immunosuppression in a large animal model.

BACKGROUND: T cells that receive T-cell antigen receptor signals but do not undergo mitosis become unresponsive to subsequent antigenic stimulation. This can be achieved by antigen presentation to T cells in the absence of critical costimulatory signals from antigen-presenting cells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes, which do not provide costimulatory signals to T cells in vitro, leads to T-cell unresponsiveness in vivo and specifically prolongs the survival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to determine whether in vivo infusion of adherent APC-depleted donor peripheral blood mononuclear cells (PBMC), with or without rapamycin, induces prolonged kidney allograft survival in a large animal model. METHODS: MHC homozygous inbred miniature swine (SLAcc) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 x 10(8) cells) from MHC disparate SLAdd donors, with and without three peritransfusion infections of rapamycin (0.25 mg/kg/day intramuscularly) the day before, the day of, and the day after the transfusion. SLAcc recipients received an SLAdd kidney transplant 6 days later. No posttransplant immunosuppression was given. RESULTS: In contrast to donor-specific whole blood transfusions, which uniformly resulted in sensitization and hyperacute rejection (less than 1 day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 +/- 4.5 days) to untreated controls (mean, 7.8 +/- 5.0 days). Pretransplant rapamycin alone also had no effect on survival (mean, 7.7 +/- 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, however, increased survival significantly (mean, 27.3 +/- 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBMC; p = 0.03 versus recipients of rapamycin alone). CONCLUSIONS: Pretransplant transfusion with costimulator-deficient donor PBMC plus peritransfusion rapamycin treatment, but neither alone, prolongs renal allograft survival in pigs without posttransplant immunosuppression. This strategy, once optimized, may be applicable to human transplant tolerance.

Animals↗
PubMed1993

The murine immune response to the male-specific antigen mouse testicular cytochrome c.

Male and female A/J mice were examined for their ability to elicit T lymphocyte and antibody (Ab) responses to the male-specific Ag, mouse testicular cytochrome c (Mt cyt). T lymphocytes from both male and female mice primed in vivo responded to the Ag in in vitro proliferation assays, and the dose-response curves were statistically indistinguishable. In addition, similar levels of Ab to Mt cyt were observed in immunized male and female mice. The B cells producing the Ab had switched isotypes to IgG1 and IgG2a, indicating that the self-reactive T helper (Th) cells in male mice were functional. Thus, male mice do not appear to be immunologically tolerant to Mt cyt, at least at the Th and B lymphocyte levels. No evidence for disease was found in male mice primed with Mt cyt. Major histocompatibility complex (MHC) class II-positive antigen-presenting cells are present in the testes and these were shown in vitro to process and present Mt cyt to a T cell hybridoma specific for the synthetic peptide Mt cyt 93-104. However, the hybridoma was not activated in the absence of exogenous Mt cyt 93-104 or Mt cyt, indicating that endogenous Mt cyt is not normally processed in sufficient quantity to effectively load MHC class II molecules with this particular Mt cyt-derived peptide. Notwithstanding any immunologic privilege of the testes, the lack of tolerance to Mt cyt and its failure to elicit an autoimmune disease could extend from the low levels of processed Mt cyt Ag available for T cell recognition. The T cell response elicited by Mt cyt contrasts the lack of response to mouse somatic cytochrome c which differs from Mt cyt at 13 amino acid residues and is expressed in most tissues and at higher levels.

Animals↗
PubMed1993

Accessory cell-derived signals required for T cell activation.

Various populations of accessory cells differ in their abilities to function as effective antigen-presenting cells (APC) and stimulate CD4+ T cells to produce interleukin-2. Three important factors directly related to APC potency are the expression of class II major histocompatibility complex molecules and the ability to present peptide antigens to the T cell antigen receptor, the expression of costimulatory ligands which deliver important activation signals independent of T cell receptor occupancy and the expression of adhesion molecules which promote conjugate formation so that these activation signals can be effectively delivered to the T cells. The relative importance of these accessory cell functions in T cell activation will be discussed, with an emphasis on costimulation and the CD28/B7 receptor/ligand pair. The consequence of inadequate costimulation by an otherwise effective APC in inducing T cell anergy will also be discussed.

Animals↗
PubMed1993

A single amino acid substitution in a cytochrome c T cell stimulatory peptide changes the MHC restriction element from one isotype (I-Ak) to another (I-Ek).

The binding sites of class II major histocompatibility complex (MHC) molecules can accommodate many seemingly diverse peptides. In the case of mouse class II molecules, it appears that in general, the I-A and I-E isotypes associate with different peptides. In this study we report an example where a single amino acid substitution in an I-Ak restricted peptide changes the restriction element to I-Ek. A T cell hybridoma, F6.A10, specific for the peptide 93-104 from mouse testicular cytochrome c (Mt cyt 93-104) was found to be restricted by I-Ak using class II molecule specific blocking monoclonal antibodies (mAb). The activation of this hybridoma by Mt cyt 93-104 was competitively inhibited by other peptides that bind to the I-Ak molecule but not by the peptide Mt cyt 93-104(A96) in which lysine at position 96 was substituted by alanine. This single amino acid substitution resulted in the ability of Mt cyt 93-104(A96) to activate the pigeon cytochrome c specific, I-Ek restricted, T cell hybridoma 2B4.11. The activation of 2B4.11 by Mt cyt 93-104(A96) was inhibited by peptides which bind to the I-Ek molecule but not by Mt cyt 93-104 and by mAb specific for I-Ek but not by mAb specific for I-Ak. These results suggest that the amino acid at position 96 may be an important anchor residue for both I-Ak and I-Ek binding but that peptides with different amino acid side chains are accommodated at that position by one or the other MHC class II isotype. Thus, in this particular case a single amino acid residue in the peptides determines the MHC class II isotype specificity.

Alanine↗
PubMed1993

Molecules involved in T-cell costimulation.

Maximal expression of the interleukin-2 gene in T cells depends on biochemical signals in addition to those transduced by the T cell antigen receptor. Recent work indicates that the T-cell specific molecule CD28 transduces a 'costimulatory' signal when it binds its ligand, the B7 molecule, on the surface of an antigen-presenting cell. Results from experiments performed during the past year have raised the exciting possibility that immune responses can be either inhibited or augmented by manipulation of the CD28-B7 interaction.

Animals↗
PubMed1992

The CD28 ligand, B7, enhances IL-2 production by providing a costimulatory signal to T cells.

Previous studies demonstrated that a human pre-B acute lymphoblastic leukemia cell line, NALM-6, failed to stimulate a primary MLR, despite expression of class II MHC and adhesion molecules. Here we demonstrate that this is the result of the fact that NALM-6 cells do not express the ligand for CD28, namely B7. NALM-6 transfectants that expressed high levels of B7 gained the capacity to stimulate IL-2 production by class II MHC molecule-specific alloreactive T cells and to costimulate a polyclonal population of purified T cells cultured with immobilized anti-CD3 mAb. In the presence of PMA, NALM-6 cells transfected with B7 polyclonally stimulated T cells in a cyclosporine A-resistant fashion, a property previously attributed only to agonistic anti-CD28 mAb. The gain of these functions could not be explained solely by an increased capacity of the transfectants to form conjugates with T cells, suggesting that the CD28/B7 interaction transduces a costimulatory signal in T cells.

Antigen-Presenting Cells↗
PubMed1992

The role of cell division in the induction of clonal anergy.

The interaction of antigen with lymphocyte antigen receptors can result in either clonal expansion or unresponsiveness (anergy). In 1970, Bretscher and Cohn proposed a two-signal model of lymphocyte activation to explain this paradox: antigen receptor occupancy alone could induce unresponsiveness whereas antigen receptor occupancy plus a costimulatory signal could induce immunity. Here, Marc Jenkins reviews in vitro and in vivo manifestations of clonal anergy and evaluates the ability of the two-signal model to explain these phenomena.

Animals↗
PubMed1992

nef-naf nexus?

Explore the source record for details and available documents.

Journal Article↗
PubMed1992

Self-reactive T cells are present in the peripheral lymphoid tissues of cyclosporin A-treated mice.

Cyclosporin A (CsA) prevents most immature thymocytes from progressing to a mature phenotype and blocks the deletion of T cells that express self-specific TCR in the small population of cells that achieve maturity. The latter effect may explain the paradoxical observation that this immunosuppressive drug can induce autoimmunity in irradiated rodents and humans if administered while new T cells are developing in the thymus. This study shows that the repopulation of the periphery with mature T cells is delayed in irradiated CsA-treated mice, presumably because CsA blocks T cell development in the thymus. The peripheral repertoire of these mice contained self-reactive IL-2 producing T cells that could be detected in a sensitive limiting dilution assay. In addition, self-reactive T cell hybridomas were isolated from the IL-2 receptor+ population present in CsA-treated mice. One of these hybridomas expressed a TCR V beta chain that is normally expressed on thymocytes that are deleted via recognition of self-antigens. Despite the presence of self-reactive T cells that had escaped clonal deletion, CsA-treated mice rarely developed lethal autoimmune disease, implying that a peripheral mechanism of tolerance can prevent the onset of autoimmune disease.

Animals↗
PubMed1992

Memory and anergy: challenges to traditional models of T lymphocyte differentiation.

Traditional paradigms suggest that encounter with an antigen converts naive peripheral T cells into memory cells with less stringent requirements for activation and increased capacities for lymphokine production. Recent evidence argues that this view may be over-simplified in two ways. First, an encounter with antigen in the absence of certain costimulatory factors can render a T cell anergic--that is, unable to respond to antigen under normal conditions. Second, although cells of the memory T cell population are more responsive than naive cells to some stimuli, these cells are hyporesponsive in other situations. Intrinsic resistance of memory T cells to elevation of intracellular calcium ion concentrations may contribute to their poor responsiveness to agents that activate naive cells. Thus, aspects of the costimulatory environment can determine whether a resting T cell is activated or rendered anergic and may also influence the kinds of stimuli to which a memory T cell will respond.

Animals↗
PubMed1992

Co-stimulatory functions of antigen-presenting cells.

Antigen-presenting cells, in addition to presenting processed antigen, provide co-stimulatory signals that are necessary for stimulating maximal lymphokine production by CD4+ T cells. For interleukin 2 (IL-2)-producing CD4+ T cells, the B7 molecule provides an important co-stimulatory signal through interaction with its ligand on the T-cell surface, CD28. Populations of antigen-presenting cells that express high levels of B7 (e.g., dendritic cells) are much more potent stimulators of T-cell activation than cells that fail to express B7 (e.g., resting B cells). An increase in B7 expression could therefore explain the increased accessory function gained by Langerhans cells as they leave the skin and migrate to the draining lymph node.

Antigen-Presenting Cells↗
PubMed1991

Accessory cell-derived costimulatory signals regulate T cell proliferation.

The costimulatory effects of anti-CD28 antibody or accessory cells on T cells were shown to be very similar. Both stimuli: (a) allowed T cell proliferation and IL-2 production in response to immobilized anti-CD3 antibody or antigen presented by APC whose costimulatory capacity had been damaged by fixation; and (b) stimulated cyclosporin A-resistant T cell proliferation in the presence of a phorbol ester. These similarities raise the possibility that anti-CD28 antibody binding to T cells delivers a costimulatory signal that is normally delivered by the interaction of CD28 with a complementary ligand on APC.

Adult↗
PubMed1991

Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation.

Murine Th1 clones that receive signals through their TCR in the absence of APC-derived co-stimulatory signals do not produce IL-2 and instead become anergic, i.e., they are subsequently unable to produce IL-2 in response to Ag and normal APC. The critical cellular event required to prevent the induction of this anergic state appears to be T cell proliferation. Anergy was induced when T cell clones were stimulated under conditions where both TCR occupancy and costimulatory signals were provided but where proliferation in response to the IL-2 produced was prevented. Once induced, anergy could be reversed if the T cells were allowed to undergo multiple rounds of cell division. These results show that anergy is induced as a consequence of TCR occupancy in the absence of cell division; this can be achieved either by limiting IL-2 production because of deficient provision of co-stimulatory signals or by preventing response to IL-2.

Animals↗
PubMed1991

CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells.

CD4+ T cells require two signals to produce maximal amounts of IL-2, i.e., TCR occupancy and an unidentified APC-derived costimulus. Here we show that this costimulatory signal can be delivered by the T cell molecule CD28. An agonistic anti-CD28 mAb, but not IL-1 and/or IL-6, stimulated T cell proliferation by tetanus toxoid-specific T cells cultured with Ag-pulsed, costimulation-deficient APC. Furthermore, the ability of B cell tumor lines to provide costimulatory signals to purified T cells correlated well with expression of the CD28 ligand B7/BB-1. Finally, like anti-CD28 mAb, autologous human APC appeared to stimulate a cyclosporine A-resistant pathway of T cell activation. Together, these results suggest that the two signals required for IL-2 production by CD4+ T cells can be transduced by the TCR and CD28.

Antibodies, Monoclonal↗